Homolog of epidermal growth factor receptor 2 (HER2/ErbB2) is overexpressed in cancers of the breast, colon, and lung, and is associated with poorer patient prognosis with ~20% of breast cancers. HER2 is principally activated by heterodimerization with other members of the epidermal growth factor receptor (EGFR/ErbB) family. Tumors that also express another member of this receptor family, homolog of epidermal growth factor receptor 3 (HER3/ErbB3), can escape HER2-targeted treatment, and heterodimerization of HER2 with HER3 is particularly mitogenic. The long-term goal of this project is to gain an improved understanding of the nature of HER2-containing heterodimers and why these heterodimers are so closely linked to a variety of cancers. The first aim of this project is to determine the structure of the extracellular domains of HER2-containing heterodimers. Heterodimers of the extracellular domains of HER2 and other members of this family, with a focus on heterodimers containing HER3, will be driven and stabilized by antibody fusion proteins. The second aim of this project is to characterize the activation of nearly full-length HER2 in the context of HER2/HER3 heterodimers in vitro. I expect that these structural and biochemical studies will reveal unique aspects of the heterodimerization and activation of these receptors. As HER2 is a target of many successful cancer treatments, an improved understanding of this receptor may inform and direct current treatment strategies.